The Endocrinology and Metabolic Drugs Advisory Committee voted 10-6 against recommending approval for the combination drug -- made by Vivus -- which was shown to be effective in helping obese and overweight patients lose an average of 6% to 10% of their body weight in the company's clinical trials.

Earlier, the vote was reported as 9-7 but one panelist later said he voted in "Yes" in error.

"In terms of efficacy, it's far superior to anything on the market," said panel member Abraham Thomas, MD, an endocrinologist at Henry Ford Hospital in Detroit.

But the committee was concerned about an increased risk of psychiatric and cognitive issues uncovered in the company's trials and said there was a lack of data to rule out cardiovascular risks and the potential for birth defects in women who become pregnant while taking the drug.

In briefing documents released in advance of the hearing, FDA reviewers were more favorable than the committee seemed to be.

The FDA does not have to follow the advice of its advisory committees, but it often does. In instances of a close vote, the FDA could go either way.

Psych Effects Outweighed Success in Obesity

Vivus is seeking approval for the drug for treatment of obese men and women with a body mass index (BMI) of 30 or higher, or in overweight patients (those with a BMI of 27 or higher) who also have weight-related comorbidities such as hypertension, diabetes, dyslipidemia, or central adiposity.

The panel spent Thursday reviewing two randomized, double-blind, placebo-controlled 56-week trials in which patients were given once-daily phentermine/topiramate in one of three doses: low (3.75 mg phentermine/23 mg topiramate), middle (7.5 mg/46 mg) and high (15 mg/92 mg).

Mean reductions ranged from about 3% of body weight on the lower dose of the phentermine/topiramate combination to 11% with the highest dose. The studies also showed improvements in blood pressure, lipids, and glycemic control.

The drug combines low doses of two approved drugs: phentermine, an appetite suppressant that was the most widely prescribed obesity drug in 2009, and topiramate, an anti-seizure medication that increases the feeling of being full and satisfied.

While both agents are known to carry their own health risks, combining them in lower doses mitigates many of those risks, Vivus argued.

The panelists didn't seem to agree.

Psychiatric adverse events -- including sleep disorders, anxiety, and depression -- occurred in 21% of patients taking the highest doses of the new drug, compared with 10% of patients taking placebo. Even at the lowest dose, phentermine/topiramate was linked to a 1.5-fold greater risk for psychiatric events compared with placebo.

The risk for depression was particularly high: Patients on phentermine/topiramate were twice as likely to experience depression than those on placebo.

Topiramate, an anti-epileptic, is known to cause suicidal thoughts; however, there were no suicide attempts or suicidal behaviors in the company's trial of the combination product.

Topiramate is also linked to impaired attention and concentration, memory loss, slowed thinking, and language difficulties, and adding phentermine to the mix didn't seem to mitigate those cognitive issues. Patients taking the combination were four times more likely to experience a cognitive disorder compared with placebo. The issues went away once patients stopped taking the drug.

Panelist Michael Rogawski, MD, PhD, a neurologist who prescribes topiramate for his patients with epilepsy, said the cognitive problems will certainly be an issue if the combination drug is approved.

"It's going to be a problem and it can't be downplayed," said Rogawski, who is the chairman of the Department of Neurology at the University of California Davis in Sacramento.

Lack of Data on Pregnancy, Cardiac Issues a Problem

The panel was not satisfied with a lack of data on the possible link to birth defects if a woman were to become pregnant while taking the drug.

In an animal study testing its teratogenicity, craniofacial malformations were detected in baby rabbits and rats. And in a U.K. study in humans that tested topiramate only, there were three cases of similar malformations.

In the company's trial, 34 women became pregnant, despite being required to commit to using two forms of birth control and to submit monthly pregnancy tests. Thirteen of those women gave birth, and no birth defects were detected, but some panel members were still concerned about approving a drug that would likely be used by millions of women of childbearing age.

"We're concerned about the high number of women who would be exposed to the drug who might have unintended pregnancies," said panel chairman Kenneth Burman, MD, an endocrinologist at Washington Hospital Center. "However," he added, "the risk for teratogenicity seems relatively low."

Cardiovascular safety was also a huge concern, largely because one half of the combination is phentermine, a component of Fen-Phen the popular fenfluramine/phentermine obesity drug that was pulled from the market about six months after its approval in 1997 because of an increased risk of heart valve problems.

Data from the company's trials didn't indicate an increased risk of valvulopathy, although the drug did increase heart rate.

The concern for panelists wasn't negative cardiovascular risk data, but lack of data.

The company had only a year of follow-up data, and some advisory committee members were concerned that longer follow-up might reveal a cardiovascular safety signal.

A spokesman for Vivus told reporters that the company expects to have two-year follow-up data by the end of September.

"Weight loss drugs have a checkered history with regard to cardiovascular risks," said panelist Sanjay Kaul, MD, a cardiologist at Cedar Sinai Medical Center in Los Angeles. "We don't have enough evidence here to evaluate cardiovascular risk other than increased heart rate."

Eric Coleman, deputy director of the FDA division that oversees metabolic drugs, said he was surprised by the vote. "But you learn in an advisory committee that you never know which way it is going to go," he said.

Coleman said it was clear a lot of panelists weren't strongly against the drug but just had enough "lingering concerns to make them vote No."

Several patients who were enrolled in Vivus' trial pleaded with the committee earlier in the day to approve the drug.

Erin Aycock, a young woman who took lost 50 pounds while taking the phentermine/topiramate combination but gained back most of the weight when the trial was over, said the drug made losing weight easier than anything else she has tried.

"It's like instant willpower," Aycock said. "I had the ability for the first time in my life to say 'I don't even care if I eat that cookie.'"

"I would do anything to be back on this drug," she said.

Weight-Loss Drugs Are Troubled Group

Two other weight-loss drugs are also up for FDA hearings later in the year -- a combination of bupropion and naltrexone (Contrave) and a combination of benzazepine and hydrochloride (Lorcaserin).

Diet drugs have a history of harmful side effects. Along with fenfluramine, dexfenfluramine (Redux) was also withdrawn from the market in 1997 for similar concerns.

Ten years later, drugmaker sanofi-aventis withdrew its new drug application for rimonabant (Zimulti) -- marketed in Europe as Accomplia -- after associated reports of depression and suicide.

And the two drugs currently approved for long-term weight loss have also raised concerns about their side effects.

Some research suggests that sibutramine (Meridia) may be linked to increased blood pressure, heart rate, and heart attacks, and orlistat (Xenical, Alli) was recently slapped with a label change to reflect an increased risk of liver injury.

In a statement sent by Vivus after the vote, the company said it was disappointed with the outcome of the meeting.

"... the final vote was close, and we are encouraged that the committee recognized the efficacy demonstrated in the Qnexa clinical trials," said Leland Wilson, CEO of Vivus.

Wilson said the company would work closely with the FDA to address safety questions raised by the committee.

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